Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim status
2. Claims 1-20 currently pending and under exam herein.
Claims 1-20 are rejected.
Priority
3. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Application is a United States national phase under 35 USC 371 of International Patent Application No. PCT/KR2020/010853 filed August 19, 2020, which in turn claims priority under 35 USC 119 of each of Korean Patent Application No. 10-2019-0101246 filed August 19, 2019, Korean Patent Application No. 10-2019-0160407 filed December 5, 2019, and Korean Patent Application No. 10-2020-0103240 filed August 18, 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
In this action, all claims are examined as though they had an effective filing date of 08/19/2019. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosures of the priority applications.
Information Disclosure Statement
4. The 8 information disclosure statements (IDSs) submitted on 03/22/2025 (x 2), 08/09/2023, 04/11/2023, 05/24/2022 and 2/14/2022 (x 3) are being considered by the examiner.
Drawings
5. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Figures 2, 3, 4, 9, 12 and 14-17 are in color.
Specification
6. Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract should not contain statements on the alleged merits or value of the claimed invention (see MPEP 1826). The abstract states that “the conventional method has decreasing accuracy when read count decreases” and that “the present invention is useful since the accuracy of the detection can increase even if the read count decreases.” Additionally, the abstract should avoid phrases which can be implied (see MPEP 6.16). The abstract recites “the present invention relates to”, which can be implied.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
7. This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such limitations are directed to ‘a decoder configured to extract nucleic acids and decode sequence information, an aligner configured to align the sequence to a reference genome and a chromosomal abnormality determiner configured to measure distance between nucleic acid fragments to determine a chromosomal abnormality’ in Claim 19.
Because this claim limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation recites sufficient structure to perform the claimed function so as to avoid it being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
The specification discloses a decoder, an aligner, and a chromosomal abnormality determiner and the function of each component (para. 0019, 0027, 0178, and 253). However no structure is provided in the specification. For the purpose of examination and under the broadest reasonable interpretation, the components will be considered to be as follows:
A decoder: Any laboratory instrument capable of extracting nucleic acids from a biological sample, which can either be manual or automated, paired with any laboratory instrument capable of obtaining sequence information from extracted nucleic acids.
An aligner: Any processor and computer-readable storage medium paired with any software or instructions capable of generating alignments of sequence reads with a reference genome database.
A chromosomal abnormality determiner: Any processor and computer-readable storage medium paired with any software or instructions configured to measure the distance between the aligned reads among the selected sequence information (reads) to calculate a read distance (RD), to calculate a read distance index (RDI) over the entire chromosomal region or each specific genomic region based on the calculated RD, and to determine that there is a chromosomal abnormality when the RDI does not fall within a cutoff value range.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
8. Claims 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 19 is directed to a device for determining a chromosomal abnormality, the device comprising: a decoder, an aligner and a chromosomal abnormality determiner and is being interpreted as a means function (as described in section 7 of this office action). This claim recites only function (what the components are configured to do) but not the structure of the components. The specification also only recites function of the device components (para. 0019, 0027, 0178, and 253), but does not describe the structure of the components (a decoder, an aligner and a chromosomal abnormality determiner).
Claim 20 is directed a computer-readable storage medium including an instruction configured to be executed by a processor for detecting a chromosomal abnormality through steps A-D, wherein step A is extracting nucleic acids from a biological sample and obtaining nucleic acid fragments to obtain sequence information. The structure of the processor is not defined in the specification, but a processor as known to one of ordinary skill in the art is not capable of nucleic acid extraction, or obtaining nucleic acid fragments.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
9. Claims 3-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 is rejected because limitation “A device for determining a chromosomal abnormality, the device comprising: a decoder, an aligner and a chromosomal abnormality determiner” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The structure of the device and its components (a decoder, an aligner and a chromosomal abnormality determiner) are not described in the claim or in the specification. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claim 3 is rejected because it is unclear if the claim intended to require carrying out the claimed sequencing steps as part of the claimed invention or if they are merely defining the process by which the nucleic acid fragments were previously obtained outside the metes and bounds of the claimed invention. Claims 4-18 depend from claim 3 and are similarly rejected because they fail to resolve the indefiniteness issue of claim 3.
Claim 7 is rejected as being indefinite because it refers to ‘a median of the nucleic acid fragment’. It is unclear to what aspect of the nucleic acid fragment that ‘median’ pertains (for example, length or position or another aspect). Claims 8-9 and 12-13 are similarly rejected because they fail to resolve the indefiniteness issue of claim 7.
Claim 12 is rejected as being indefinite because it is unclear what “the nucleic acid to be analyzed” is pertaining to. For example, is it referring to the nucleic acid fragment?
Claim 14 is rejected as being indefinite because the limitation in step Eii introduces both ‘a certain region in a sample’ and ‘the specific genomic region’, but it is unclear how these are different from each other. Dependent claims 15-18 are similarly rejected because they fail to resolve the indefiniteness issue of claim 14.
Claims 19 and 20 are rejected as being indefinite due to lack of antecedent basis because it is unclear to what ‘the selected nucleic acid fragments’ refers. Selected nucleic acid fragments have not been introduced in the claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
10. Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 2A, Prong 1
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1 recites: calculating a distance between Representative Positions of nucleic acid fragments extracted from a biological sample
Claim 2 recites: wherein the nucleic acid fragments are cell-free nucleic acids or intracellular nucleic acids
Claim 3 recites: wherein the nucleic acid fragments are obtained by direct sequencing, next-generation sequencing, or sequencing through non-specific whole-genome amplification
Claim 4C recites: grouping the sequence information (reads) into whole sequences, forward sequences, and reverse sequences
Claim 4D recites: defining Representative Positions of the respective nucleic acid fragments using the grouped sequence information
Claim 4D recites: measuring the distance between the Representative Positions to calculate a fragment distance (FD) for each group
Claim 4E recites: calculating a fragment distance index (FDI) for the entire chromosomal region or each specific region based on the FD for each group calculated in step (D)
Claim 4E recites: determining that there is a chromosomal abnormality when the FDI does not fall within a cutoff value range
Claim 6 recites: wherein the FD in step (D) is calculated as a distance between the Representative Position of an ith nucleic acid fragment and the Representative Position of at least one nucleic acid fragment selected from i+lth to nth nucleic acid fragments among obtained n nucleic acid fragments
Claim 7 recites wherein the Representative Position of the nucleic acid fragment is obtained by adding an arbitrary value to a median of the nucleic acid fragment or subtracting the arbitrary value therefrom
Claim 8 recites wherein, in paired-end sequencing, the Representative Position of the nucleic acid fragment is derived based on position values of forward and reverse reads
Claim 9 recites excluding nucleic acid fragments having a mapping quality score of reads below a cutoff value from calculation
Claim 10 recites wherein in single-end sequencing, the Representative Position of the nucleic acid fragment is derived based on one type of position value of forward or reverse read
Claim 11 recites wherein an arbitrary value is added when a position value is derived based on sequence information aligned in the forward direction and the arbitrary value is subtracted when a position value is derived based on sequence information aligned in the reverse direction
Claim 12 recites wherein the arbitrary value is 30 to 70% of a mean length of the nucleic acid to be analyzed
Claim 13 recites wherein the arbitrary value is 0 to 5 kbp or 0 to 300% of a length of the nucleic acid fragment
Claim 14E-i recites determining a representative FD (RepFD) for an entire chromosomal region or for each specific region
Claim 14E-ii recites calculating one or more selected from the group consisting of a sum, difference, product, mean, log of product, log of sum, median, quantile, minimum, maximum, variance, standard deviation, median absolute deviation and coefficient of variance of RepFD, reciprocals thereof and a combination thereof in a certain region in the sample, rather than the entire chromosomal region or specific genomic region, to derive a normalized factor
Claim 14E-iii recites calculating a representative FD ratio (RepFD ratio) based on Equation 1 below; and Equation 1 recites RepFD ratio = RepFD Target genomic region / Normalized Factor
Claim 14E-iv recites comparing the RepFD ratio of a normal reference group with that of the sample to calculate a fragment distance index (FDI)
Claim 15 recites wherein the representative FD (RepFD) of step (E-i) is at least one selected from the group consisting of a sum, difference, product, mean, log of product, log of sum, median, quantile, minimum, maximum, variance, standard deviation, median absolute deviation and coefficient of variance of FDs, and/or a reciprocal thereof
Claim 16 recites wherein the representative FD (RepFD) of step (E-i) is a median, mean, or reciprocal of FD
Claim 17a recites: randomly selecting a region other than an entire chromosomal region or a specific genomic region to be analyzed
Claim 17b recites: determining a representative RepFD of the genomic region selected in step a) with a pre-normalized factor (PNF)
Claim 17c recites: calculating a representative FD ratio (RepFD ratio) based on Equation 2. Equation 2: RepFD ratio = RepFD Target genomic region / PNF
Claim 17d recites: calculating a coefficient of variance (SD/mean) of the RepFD ratio of a normal reference group
Claim 17e recites: determining a genomic region having a smallest value among obtained coefficients of variance obtained by repeatedly performing steps a) to d) as the certain region in the sample, other than the entire chromosomal region or the specific genomic region
Claim 18 recites: comparing the RepFD ratio of the normal reference group with the RepFD ratio of the sample
Claim 19 recites: a chromosomal abnormality determiner configured to measure the distance between the aligned nucleic acid fragments among the selected nucleic acid fragments to thereby calculate a fragment distance (FD)
Claim 19 recites: a chromosomal abnormality determiner configured to calculate a fragment distance index (FDI) over the entire chromosomal region or each specific genomic region based on the calculated FD
Claim 19 recites: a chromosomal abnormality determiner configured to determine that there is a chromosomal abnormality when the FDI does not fall within a cutoff value range
Claim 20C recites: storage of instructions for measuring the distance between the selected nucleic acid fragments to calculate a fragment distance (FD)
Claim 20D recites: storage of instructions for calculating a fragment distance index (FDI) over the entire chromosomal region or in each specific genomic region based on the FD calculated in step (C) and determining that there is a chromosomal abnormality when the FDI does not fall within a cutoff value range
The limitations regarding: calculating or measuring a distance between nucleic acid fragments, measuring the distance between the Representative Positions, calculating a fragment distance index (FDI) for the chromosomal region, adding or subtracting an arbitrary value to/from a median, calculating a normalization factor, and calculating a representative FD, calculating an FD ratio, comparing ratios to get an FDI, and calculating a coefficient of variance are verbal equivalents that describe mathematical calculations that are performed as the limitation and are so simple that they could be performed with a pen and paper. Therefore, these limitations fall under the “Mathematical concepts” and “Mental process” grouping of abstract ideas. The limitations for identifying positions of the nucleic acid fragments in a reference genome database, defining Representative Positions of nucleic acid fragments determining a representative FD (RepFD) for a chromosomal region, grouping the sequence information (reads), determining that there is a chromosomal abnormality, excluding nucleic acid fragments based on mapping quality score, selecting a region and determining a genomic region are generically recited data analysis steps that can be practically performed in the human mind because the human mind is capable of identifying relevant information, defining values, determining representative values, grouping data, comparing data, excluding data. Therefore, these limitations fall into the “Mental process” grouping of abstract ideas. Limitations that further limit the type or source of the nucleic acids, the type of sequence data used, which nucleic acid fragments are analyzed, the types of sequencing reads used, the chromosomal region being compared, and the threshold of arbitrary values that can be added or subtracted to fragment positions do not change the limitations from being “Mathematical concepts” and/or “Mental processes”.
While claims 19 and 20 recites a device for performing the extra solution activity steps (a decoder and aligner for data gathering), there are no additional limitations that indicate that this device requires anything other than standard laboratory equipment for carrying out the recited data gathering. Additionally, while claims 19 and 20 recite computer-readable storage medium with instructions to perform some aspects of the analysis with a processor, there are no additional limitations that indicate that this processor requires anything other than carrying out the recited mental process or mathematical concept in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation of generic computer components, then if falls within the "Mental processes" grouping of abstract ideas. As such, claims 1-20 recite an abstract idea (Step 2A, Prong 1: YES).
Step 2A, Prong 2
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies or uses the recited judicial exception in some other meaningful way. Rather, the instant claims recite additional elements that amount to mere instructions to implement the abstract idea in a generic computing environment, or insignificant extra-solution activity with generic laboratory tools. Specifically, the claims recite the following additional elements:
Claim 4A recites: extracting nucleic acids from a biological sample and obtaining nucleic acid fragments to obtain sequence information therefrom
Claim 4B recites: identifying positions of the nucleic acid fragments in a reference genome database based on the obtained sequence information (reads)
Claim 5A-i recites: obtaining nucleic acids from blood, semen, vaginal cells, hair, saliva, urine, oral cells, amniotic fluid containing placental cells or fetal cells, tissue cells, and a mixture thereof
Claim 5A-ii recites: removing proteins, fats, and other residues from the collected nucleic acids using a salting-out method, a column chromatography method, or a bead method to obtain purified nucleic acids
Claim 5A-iii recites: producing a single-end sequencing or pair-end sequencing library for the purified nucleic acids or nucleic acids randomly fragmented by an enzymatic digestion, pulverization, or hydroshear method
Claim 5A-iv recites: reacting the produced library with a next- generation sequencer
Claim 5A-v recites: obtaining sequence information (reads) of the nucleic acids in the next-generation sequencer
Claim 19 recites: an aligner configured to align the decoded sequence to a reference genome database
Claim 19 recites: a decoder configured to extract nucleic acids from a biological sample and decode sequence information
Claim 20A recites: a computer-readable storage medium including instructions for extracting nucleic acids from a biological sample and obtaining nucleic acid fragments to obtain sequence information
Claim 20B recite: a computer-readable storage medium including instructions for aligning the nucleic acid fragments to a reference genome database based on the obtained sequence information (reads)
The limitations for extracting nucleic acids from a biological sample, obtaining nucleic acids from samples, removing proteins, fats, and other residues from the collected nucleic acids, producing a single-end sequencing or pair-end sequencing library for the purified nucleic acids or fragments, reacting the produced library with a next- generation sequencer, obtaining or decoding sequence information (reads) and aligning nucleic acid fragments (or identifying positions of nucleic acid fragments or aligning decoded sequences) merely serve to gather data that is used as an input for the judicial exception. The use of generic laboratory devices for DNA extraction and sequencing and the use of generic tools for sequence alignment do not add a practical application. Supporting the generality of these steps of the claimed method, it is disclosed in the specification that in the present invention, various known devices for sequencing and various known algorithms for sequence alignment may be used (para. 0104 – 0114; para. 0057, 0079). Therefore, these limitations are mere data gathering activities. As set forth in MPEP 2106.05(g), mere data gathering activity has been identified by the courts as insignificant extra-solution activity that does not provide a practical application. There are no limitations that indicate that the processor or computer-readable storage requires anything other than a generic computing system. As such, these limitations equate to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984.
The above recited additional elements do not provide a practical application of the recited judicial exception. As such, claims 1-20 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to mere instructions to apply the recited exception in a generic computing environment or well-understood, routine and conventional activity. As discussed above, there are no additional limitations to indicate that the claimed processor requires anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. Furthermore, the additional elements recited in the claims amount to well-understood, routine and conventional activity, including: 1) procurement and purification of nucleic acids from biological samples, as described in standard biobanking protocols (Yong, Springer protocols, Methods in Molecular Biology, 2018, p. 1-445, chapters 9-14, 30); 2) preparation of nucleic acid samples for next generation sequencing and conducting next generation sequencing (Yong, Springer protocols, Methods in Molecular Biology, 2018, p. 1-445, Chapter 31); 3) generation of single-end and paired-end sequencing libraries and obtaining sequence information by next-generation sequencing (Head et al. BioTechniques, Vol 52, No. 2, 2014, p. 61-77); 4) alignment of nucleic acid fragments to a genomic sequence (Yong, Springer protocols, Methods in Molecular Biology, 2018, p. 1-445, Chapter 29 and 31) and 5) storing and retrieving information in memory, Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93. Furthermore, it is stated in the specification of the instant application that the present invention uses Next-generation sequencing known in the art that is commercially available (para. 0057, 0079). As such, the combination of additional elements recited in the claims is well-understood, routine and conventional.
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-20 are not patent eligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
11. Claims 1-3 and 19-20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being unpatentable over Talkowski et al. (US 2015/0286773 A1; 4/11/2023 IDS Document). The italicized text corresponds to the instant claim limitations.
With respect to claim 1, Talkowski et al. discloses a method of prenatal determination of chromosomal abnormalities whereby genomic DNA extracted from cells in an amniotic fluid sample (a biological sample) and fragmented. Talkowski et al. further discloses generating a large-insert jumping library for the subject, aligning paired-end sequence reads against a reference genome, flagging “anomalous” read pairs that align to genomic sequences separated by significantly greater than or less than the size of the DNA fragments selected for the library generation (para. 0007, 0064; a method of detecting a chromosomal abnormality, the method comprises: calculating a distance between Representative Positions of nucleic acid fragments extracted from a biological sample).
Regarding claim 2, Talkowski et al. discloses that genomic DNA extracted from cells in an amniotic fluid sample (para. 0007, wherein the nucleic acid fragments are cell-free nucleic acids or intracellular nucleic acids).
Regarding claim 3, Talkowski et al. discloses that the large-insert jumping library can be sequenced by paired-end sequencing, de novo sequencing, next generation sequencing or any technology known in the art (para. 0060, wherein the nucleic acid fragments are obtained by direct sequencing, next-generation sequencing, or sequencing through non-specific whole-genome amplification).
Regarding claim 19, Talkowski et al., discloses a computing module comprising instructions to determine structural rearrangements from the sequence comparison analysis including a determination module configured to receive test samples and perform sequencing analysis. It is further disclosed that genomic DNA is extracted from cells in amniotic fluid samples (para. 0007, 0011, Fig. 9, A device for determining a chromosomal abnormality, the device comprising: a decoder configured to extract nucleic acids from a biological sample and decode sequence information).
Talkowski et al. further discloses that the computing module includes instructions for mapping read-pairs of the output sequence data against a reference genome (para. 0011, an aligner configured to align the decoded sequence to a reference genome database).
Talkowski et al. discloses that the computing module determines chromosome abnormalities by calculating fragment distances for read pairs and categorizing read-pairs into clusters and determining the distance between the maximum and minimum mapping positions on both ends of the cluster (para. 0010-0011; a chromosomal abnormality determiner configured to measure the distance between the aligned nucleic acid fragments among the selected nucleic acid fragments to thereby calculate a fragment distance (FD).
Regarding the limitations pertaining to FDI, FDI is considered to be any measurement that compares the fragment distance of a group of fragments representing a putative structural anomaly to a that of a normal reference group. Talkowski et al. discloses a computational pipeline with various modules for identifying structural variants from the aligned sequence data by comparing fragment distances of potentially anomalous groups to those of normal reference groups. Talkowski et al. discloses identifying and categorizing as ‘anomalous’, read pairs that align to genomic sequences separated by significantly greater than or less than the size of the DNA fragments selected for library creation and grouping anomalous read pairs into clusters of fragments representing putative structural variant breakpoints. Two analyses are disclosed to characterize these clusters that embody calculating an FDI. First, Talkowski et al. discloses analyzing a clusters by determining a normalized distance between the maximum and minimum mapping positions on both ends of cluster calibrated to the library size (i.e. average fragment size) and analyzing these data using a random forest classifier to determine if the putative anomaly is valid or invalid (with probability assignments). Second, Fragments representing a putative chromosomal abnormality (with abnormal distances) are grouped separately from fragments in the same chromosomal position representing a normal (or ‘proper’) chromosome (with the expected distances). The ratio of the number fragments with abnormal distances to the number of proper fragments (both locally and globally) is calculated. Talkowski et al. further discloses that these distances and ratios are used to classify the presence or absence of a structural variant in a region of DNA (with probability assignments). This can be done using a random forest classification program including inter-sample comparisons to control samples. In both embodiments, the probability of a valid variant assigned by the classifier is equivalent to an FDI (para. 0010-0011, 0064, 0208-0209, and 0279-0331; a chromosomal abnormality determiner configured to calculate a fragment distance index (FDI) over the entire chromosomal region or each specific genomic region based on the calculated FD, and to determine that there is a chromosomal abnormality when the FDI does not fall within a cutoff value range).
Regarding claim 20, Talkowski et al. discloses that the system for analyzing the sequence data includes a storage device configured to store output sequence data from the analysis and instructions for processing and analyzing samples including: instructions for the determination module (for determining sequence for large-insert jumping libraries from a target cell) and instructions for the computing module (for performing the analysis to determine structural anomalies). Talkowski et al. further discloses that the system categorizes read-pairs into clusters and determining the distance between the maximum and minimum mapping positions on both ends of the cluster. Talkowski further discloses that read pairs that align to genomic sequences separated by significantly greater than or less than the size of the DNA fragments selected for library creation are categorized as anomalous. (para. 0011, 0064, Fig. 9, A computer-readable storage medium including an instruction configured to be executed by a processor for detecting a chromosomal abnormality through the following steps comprising: (A) extracting nucleic acids from a biological sample and obtaining nucleic acid fragments to obtain sequence information (B) aligning the nucleic acid fragments to a reference genome database based on the obtained sequence information (reads); (C) measuring the distance between the selected nucleic acid fragments to calculate a fragment distance (FD)).
Regarding claim 20 limitation D, FDI is considered to be any measurement that compares the fragment distance of a group of fragments representing a putative structural anomaly to a that of a normal reference group. Talkowski et al. discloses a computational pipeline with various modules for identifying structural variants from the aligned sequence data by comparing fragment distances of potentially anomalous groups to those of normal reference groups. Talkowski et al. discloses identifying and categorizing as ‘anomalous’, read pairs that align to genomic sequences separated by significantly greater than or less than the size of the DNA fragments selected for library creation and grouping anomalous read pairs into clusters of fragments representing putative structural variant breakpoints. Two analyses are disclosed to characterize these clusters that embody calculating an FDI. First, Talkowski et al. discloses analyzing a clusters by determining a normalized distance between the maximum and minimum mapping positions on both ends of cluster calibrated to the library size (i.e. average fragment size) and analyzing these data using a random forest classifier to determine if the putative anomaly is valid or invalid (with probability assignments). Second, Fragments representing a putative chromosomal abnormality (with abnormal distances) are grouped separately from fragments in the same chromosomal position representing a normal (or ‘proper’) chromosome (with the expected distances). The ratio of the number fragments with abnormal distances to the number of proper fragments (both locally and globally) is calculated. Talkowski et al. further discloses that these distances and ratios are used to classify the presence or absence of a structural variant in a region of DNA (with probability assignments). This can be done using a random forest classification program including inter-sample comparisons to control samples. In both embodiments, the probability of a valid variant assigned by the classifier is equivalent to an FDI (para. 0010-0011, 0064, 0208-0209, and 0279-0331; (D) calculating a fragment distance index (FDI) over the entire chromosomal region or in each specific genomic region based on the FD calculated in step (C) and determining that there is a chromosomal abnormality when the FDI does not fall within a cutoff value range).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
12. Claims 4-6 and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over Talkowski et al. (US 2015/0286773 A1; 04/11/2023 IDS document), as applied to claims 1-3 above, as evidenced by Kappal (Kappal, Compilation 1.0, Vol. 19, Iss. 4, p. 39-44). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-3 are taught by Talkowski et al. above.
Regarding claim 4, Talkowski et al. teaches a method comprised of the limitations of claim 4 as summarized in para. 0011 and 0064. Details of each step are described below as they pertain to each specific limitation.
Regarding claim 4A, Talkowski et al. discloses extracting genomic DNA from cells in an amniotic fluid sample and obtaining nucleic acid fragments from the genomic DNA. Talkowski et al. further discloses using paired-end sequencing, de novo sequencing, next generation sequencing or another technology to sequence the fragmented large-insert jumping library (para. 0007, 0041-0043, 0060; (A) extracting nucleic acids from a biological sample and obtaining nucleic acid fragments to obtain sequence information therefrom).
Regarding claim 4B, Talkowski et al. disclose that paired-end sequence reads obtained from the whole-genome sequence analysis are aligned against sequence of at least one or more chromosomes. Talkowski et al. further discloses that the mapping positions of aligned fragments are used for structural variant identification (para. 0011, 0064; (B) identifying positions of the nucleic acid fragments in a reference genome database based on the obtained sequence information (reads)).
Pertaining to claim 4C, the specification of the instant application indicates that groups corresponding to forward sequences, reverse sequences and whole sequences can refer to nucleic acid fragments aligned in a forward direction, a reverse direction, or together for the whole group, respectively. Talkowski et al. discloses that read-pairs can be categorized into clusters based on a ‘mapping quality score’ on both ends of the cluster and the residual between the measurements or based on ‘alignability percent averaging’ across sequences of both ends of the cluster and the residual between both measurements. This disclosed clustering is inclusive of clustering together those reads with high quality forward and reverse sequences (i.e. whole sequences), and clustering separately those with only aligned forward or reverse sequences due to low quality mapping or low alignment of either the forward or reverse read (para. 0011, 0182, 0186, 0193); (C) grouping the sequence information (reads) into whole sequences, forward sequences, and reverse sequences).
With respect to claim 4D, Talkowski et al. discloses mapping read-pairs of the sample sequence data against a reference genome to determine mapping positions. Talkowski et al. further describes calculating distances for specific pairs of reads and categorizing as anomalous, those read pairs that align to genomic sequences separated by significantly greater or less than the size of the DNA fragments selected for library creation. Talkowski et al. further discloses clustering read pairs categorized as anomalous and calculating the distance (and normalized distance) between the maximum and minimum mapping positions on both ends of the cluster (para. 0011 and 0064c (D) defining Representative Positions of the respective nucleic acid fragments using the grouped sequence information, and measuring the distance between the Representative Positions to calculate a fragment distance (FD) for each group).
Regarding claim 4E, FDI is considered to be any measurement that compares the fragment distance of a group of fragments representing a putative structural anomaly to a that of a normal reference group. Talkowski et al. discloses a computational pipeline with various modules for identifying structural variants from the aligned sequence data by comparing fragment distances of potentially anomalous groups to those of normal reference groups. Talkowski et al. discloses identifying and categorizing as ‘anomalous’, read pairs that align to genomic sequences separated by significantly greater than or less than the size of the DNA fragments selected for library creation and grouping anomalous read pairs into clusters of fragments representing putative structural variant breakpoints. Two analyses are disclosed to characterize these clusters that embody calculating an FDI. First, Talkowski et al. discloses analyzing a clusters by determining a normalized distance between the maximum and minimum mapping positions on both ends of cluster calibrated to the library size (i.e. average fragment size) and analyzing these data using a random forest classifier to determine if the putative anomaly is valid or invalid (with probability assignments). Second, Fragments representing a putative chromosomal abnormality (with abnormal distances) are grouped separately from fragments in the same chromosomal position representing a normal (or ‘proper’) chromosome (with the expected distances). The ratio of the number fragments with abnormal distances to the number of proper fragments (both locally and globally) is calculated. Talkowski et al. further discloses that these distances and ratios are used to classify the presence or absence of a structural variant in a region of DNA (with probability assignments). This can be done using a random forest classification program including inter-sample comparisons to control samples. In both embodiments, the probability of a valid variant assigned by the classifier is equivalent to an FDI (para. 0010-0011, 0064, 0208-0209, and 0279-0331; (E) calculating a fragment distance index (FDI) for the entire chromosomal region or each specific region based on the FD for each group calculated in step (D) and determining that there is a chromosomal abnormality when the FDI does not fall within a cutoff value range).
Regarding claim 4D and 4E, for groups that have only forward or reverse sequences and not both forward and reverse sequences, Talkowski et al. teaches that the method of variant detection is compatible with such groups. Talkowski et al., teaches that the method can use data from platforms that do not generate paired-end reads, including massively parallel signature sequencing (MPSS), pyrosequencing and microfluidic Sanger sequencing. Talkowski et al. is silent to specifying a method of identifying variants specifically for single-end reads, but following their disclosed method for paired-end reads, but substituting ‘reads’ for ‘paired-end reads’, their method is compatible with SE reads as follows: Talkowski et al. discloses identifying clusters of reads representing putative structural variants using features that are not specific to paired-end reads such as: 1) a global coverage ratio of the number of the reads in the cluster to the average haploid proper pair coverage in the reference genome; 2) number of reads in the cluster 3) mapping quality scores on both ends of the cluster and the residual between both measurements. Talkowski et al. further discloses measuring the normalized distance between the maximum and minimum mapping positions on both ends of the cluster and inputting the measured features of the cluster into a random forest classifier to predict the presence of a structural variant (including a probability score). Talkowski et al. further discloses that classification can involve inter-sample comparisons to control samples (0060, 0071, 0011, 0208, 209 and 0315, (D) defining Representative Positions of the respective nucleic acid fragments using the grouped sequence information, and measuring the distance between the Representative Positions to calculate a fragment distance (FD) for each group); (E) calculating a fragment distance index (FDI) for the entire chromosomal region or each specific region based on the FD for each group calculated in step (D) and determining that there is a chromosomal abnormality when the FDI does not fall within a cutoff value range).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to simply substitute reads for paired-end reads in the invention of Talkowski et al. in order to identify structural variants using single-end read data. Furthermore, one of ordinary skill in the art would predict that single-end data could be readily added to the system of Talkowski et al. with a reasonable expectation of success because they disclose that it is compatible with single-end read data (0060). The invention is therefore prima facie obvious.
Regarding claim 5, Talkowski et al. discloses examples of tissue that can be used for extraction of genomic DNA can include, but are not limited to, blood, lung, heart, liver, skin, pancreas, or tissue of any organs (A-i). Talkowski et al. discloses that after PCR amplification, DNA libraries are purified using a magnetic stand to separate post-PCR solution from the beads using a purification kit (such as Qiagen PCR purification column), and further purifying by gel extraction using a Qiagen gel purification reagents (A-ii). Talkowski et al. further discloses that the large-insert jumping library can be generated by paired-end sequencing and that the library can be produced by shearing genomic DNA or by partial or complete digestion with endonucleases or restriction endonucleases (A-iii). Talkowski et al., discloses that the library can be sequenced using a next-generation sequencer (A-iv) and that raw sequencing reads are collected (A-v) (para. 0043, 0060, 0074, 0268-0269, 0280, wherein the step (A) comprises:(A-i) obtaining nucleic acids from blood, semen, vaginal cells, hair, saliva, urine, oral cells, amniotic fluid containing placental cells or fetal cells, tissue cells, and a mixture thereof, (A-ii) removing proteins, fats, and other residues from the collected nucleic acids using a salting-out method, a column chromatography method, or a bead method to obtain purified nucleic acids; (A-iii) producing a single-end sequencing or pair-end sequencing library for the purified nucleic acids or nucleic acids randomly fragmented by an enzymatic digestion, pulverization, or hydroshear method; (A-iv) reacting the produced library with a next-generation sequencer; and (A-v) obtaining sequence information (reads) of the nucleic acids in the next-generation sequencer).
Pertaining to claim 6, Talkowski et al. discloses clustering read pairs categorized as anomalous at a putative structural variant break point and calculating the distance between the maximum and minimum mapping positions on both ends of the cluster, and using these data to determine presence of a valid structural rearrangement. Clustering multiple reads together and calculating the distance between the maximum and minimum position is a method measuring distance between Representative Positions between different nucleic acid fragments. (para. 0010-0011 and 0064c; wherein the FD in step (D) is calculated as a distance between the Representative Position of an it nucleic acid fragment and the Representative Position of at least one nucleic acid fragment selected from i+1t to n* nucleic acid fragments among obtained n nucleic acid fragments).
Regarding claim 14 limitation E(i), Talkowski et al. discloses categorizing anomalous read pairs into the same cluster if both sides of the read pairs align within a selected distance of each other; wherein each output cluster represents a putative structural variant breakpoint. Talkowski et al. further discloses calculating a distance between the maximum and minimum mapping positions on both ends of the cluster (para. 0010-0011, (E-i) determining a representative FD (RepFD) for an entire chromosomal region or for each specific region).
Regarding claims 14 limitations E (ii-iv) and claim 18, FDI is considered to be any measurement that compares the fragment distance of a group of fragments representing a putative structural anomaly to a that of a normal reference group. Talkowski et al. discloses a computational pipeline with various modules for identifying structural variants from the aligned sequence data by comparing fragment distances of potentially anomalous groups to those of normal reference groups. Talkowski et al. discloses identifying and categorizing as ‘anomalous’, read pairs that align to genomic sequences separated by significantly greater than or less than the size of the DNA fragments selected for library creation and grouping anomalous read pairs into clusters of fragments representing putative structural variant breakpoints. Two analyses are disclosed to characterize these clusters that embody calculating an FDI. First, Talkowski et al. discloses analyzing a clusters by determining a normalized distance between the maximum and minimum mapping positions on both ends of cluster calibrated to the library size (i.e. average fragment size) and analyzing these data using a random forest classifier to determine if the putative anomaly is valid or invalid (with probability assignments). Second, Fragments representing a putative chromosomal abnormality (with abnormal distances) are grouped separately from fragments in the same chromosomal position representing a normal (or ‘proper’) chromosome (with the expected distances). The ratio of the number fragments with abnormal distances to the number of proper fragments (both locally and globally) is calculated. Talkowski et al. further discloses that these distances and ratios are used to classify the presence or absence of a structural variant in a region of DNA (with probability assignments). This can be done using a random forest classification program including inter-sample comparisons to control samples. In both embodiments, the probability of a valid variant assigned by the classifier is equivalent to an FDI (para. 0010-0011, 0064, 0208-0209, and 0279-0331; (E-ii) calculating one or more selected from the group consisting of a sum, difference, product, mean, log of product, log of sum, median, quantile, minimum, maximum, variance, standard deviation, median absolute deviation and coefficient of variance of RepFD, reciprocals thereof and a combination thereof in a certain region in the sample, rather than the entire chromosomal region or specific genomic region, to derive a normalized factor), (E-iii) calculating a representative FD ratio (RepFD ratio) based on Equation 1 below: Equation 1: RepFD ratio = RepFD Target genomic region / Normalized Factor); (E-iv) comparing the RepFD ratio of a normal reference group with that of the sample to calculate a fragment distance index (FDI)); claim 18, wherein step (E-iv) comprises comparing the RepFD ratio of the normal reference group with the RepFD ratio of the sample).
Talkowski et al. is silent to the specific RepFD normalization step disclosed to derive a normalization factor from a ‘certain region of the sample’ and specifically divide RepFD by this factor to get the RepFD ratio. In the first embodiment of FDI disclosed by Talkowski et al., the distance between the maximum and minimum mapping positions on both ends of cluster is normalized to the library size (i.e. the average fragment size of the library) to get the value corresponding to RepFD ratio. As evidenced by Kappal (normalization indicates division by the normalization factor (p. 39, sect. I, para. 1 ). However, the claimed method indicates that the normalization must be to one of the listed characteristics of RepFD in a certain region of the sample. The RepFD ratio calculated by Talkowski et al. can simply be substituted for the RepFD ratio of the instant application because it would yield effectively the same value. This is because it is disclosed in the specification that the certain region can be selected randomly (para. 00163 and 0239) and the ‘average fragment size of the library’ used by Talkowski et al. is effectively the same as a mean or median representative fragment distance in a randomly selected region of the alignment. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to substitute the RepFD ratio of the instant application with those of Talkowski et al. to measure length variation in a structural variant sample to identify structural variants. Furthermore, one of ordinary skill in the art would predict that the RepFD ratio taught by Talkowski et al. could be readily be substituted in the system of the present invention with a reasonable expectation of success because both inventions pertain to structural variant calling in diploid organisms by fragmenting, sequencing and genome alignment, followed by analysis of grouped aligned reads. The invention is therefore prima facie obvious.
Regarding claim 15, Talkowski et al., discloses that the representative fragment distance of a cluster of read-pairs representing a putative ‘breakpoint’ can be calculated as the maximum FD of the cluster. This is calculated by calculating the Span, which is the distance between the maximum and minimum mapping positions on both ends of a cluster of reads, which corresponds to the maximum FD of the cluster in the instant application (para. 0011, 0317, 0322; wherein the representative FD (RepFD) of step (E-i) is at least one selected from the group consisting of a sum, difference, product, mean, log of product, log of sum, median, quantile, minimum, maximum, variance, standard deviation, median absolute deviation and coefficient of variance of FDs, and/or a reciprocal thereof).
With respect to claim 16, Talkowski et al. discloses that in some embodiments, a variant call is made by using a categorizing analysis program (e.g., BamStat) and clustering analysis program (e.g. readPairCluster) to generate output clusters where each output cluster generally represents a putative structural variant breakpoint. In some embodiments these clusters are further analyzed to determine validity of the variants using machine learning machine learning. The data input into these algorithms includes insert size measurements such as mean and median insert sizes for FR and RF read-pairs, as well as standard deviation and median absolute deviation, respectively, of all proper-pairs found in the file (para. 0279-0315; wherein the representative FD (RepFD) of step (E-i) is a median, mean, or reciprocal of FDs).
Concerning claim 17 limitations a-c, Talkowski et al., discloses an example bioinformatic pipeline for whole-genome analysis that identifies structural variations in any region without pre-selecting a specific region. Talkowski et al. further discloses categorizing anomalous read pairs into the same cluster if both sides of the read pairs align within a selected distance of each other; wherein each output cluster represents a putative structural variant breakpoint. Talkowski et al. further discloses calculating a distance and a normalized distance between the maximum and minimum mapping positions on both ends of the cluster (corresponding to RepFD and repFD ratio). The normalization can be done to calibrate the distance (or span) measurement to the current library size (para. 0010-0011, 0279-0315, and 0323; wherein the certain region in the sample other than the entire chromosomal region or specific genomic region in step (E-ii) is selected using a method comprising: a) randomly selecting a region other than an entire chromosomal region or a specific genomic region to be analyzed; b) determining a representative RepFD of the genomic region selected in step a) with a pre-normalized factor (PNF); c) calculating a representative FD ratio (RepFD ratio) based on Equation 2: Equation 2: RepFD ratio = RepFD Target genomic region / PNF.
Regarding claim 17 limitations d-e, Talkowski et al. teaches for (forward-reverse) and (reverse-forward) read-pairs, calculating mean and median insert sizes, as well as standard deviation and median absolute deviation, respectively, of all proper-pairs (which correspond to normal references) (para. 300; d) calculating a coefficient of variance (SD/mean) of the RepFD ratio of a normal reference group; and e) determining a genomic region having a smallest value among obtained coefficients of variance obtained by repeatedly performing steps a) to d) as the certain region in the sample, other than the entire chromosomal region or the specific genomic region).
Talkowski et al. discloses using a variety of statistical tests in identification of structural variants, but is silent to specifically calculating coefficient of variance and determining a genomic region having a smallest value to determine a certain region of the sample. However, these steps are directed to identifying a genomic region to use as a normal reference for comparing to those with putative structural variants and Talkowski et al. proposes an alternative method that could be simply substituted. Talkowski et al. discloses that within one genomic region of an alignment of a sample with a reference genome, fragments representing a putative chromosomal abnormality (with abnormal distances) are grouped separately from a group of fragments in the same chromosomal position representing a normal (or ‘proper’) chromosome (with the expected distances). Therefore, in comparing the putative anomalous reads to proper normal reads, identifying a region of low variance of the normal reference is not necessary because the same region is used for both proper and anomalous reads. (para 0011, 0316-0328; d) calculating a coefficient of variance (SD/mean) of the RepFD ratio of a normal reference group; and e) determining a genomic region having a smallest value among obtained coefficients of variance obtained by repeatedly performing steps a) to d) as the certain region in the sample, other than the entire chromosomal region or the specific genomic region).
The method of Talkowski et al. for identifying a genomic region to use as a normal reference region is different from that in the instant application, but both methods effectively identify a normal region to use as a control for comparison to putative variants. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to substitute the components of the instant application with those of Talkowski et al. to identify normal reference regions. Furthermore, one of ordinary skill in the art would predict that the normal regions used by Talkowski et al. could be readily be substituted in the system of the present invention with a reasonable expectation of success because both inventions pertain to structural variant calling in diploid organisms by fragmenting, sequencing and genome alignment, followed by analysis of grouped aligned reads. The invention is therefore prima facie obvious.
13. Claims 7-13 are rejected under 35 U.S.C. 103 as being unpatentable over Talkowski et al. (US 2015/0286773 A1; 04/11/2023 IDS document), as applied to claims 1-6 above, and further in view of Zhang et al., Genome biology, 2008, vol. 9 issue 9, R137.1-R137.9. The italicized text corresponds to the instant claim limitations.
The limitations of claims 1-6 have been taught by Talkowski et a. as indicated above.
Claims 7 and 10-13 are directed to estimating the center position of a nucleic acid fragment in an alignment based on mean or median fragment length of the library (for example in single-end (SE) sequencing). Talkowski et al. is silent to estimating the center position of a fragment based adding or subtracting a value to the either the forward or reverse read positions based on the mean or median fragment length in claims 7 and 11-13 . However, these limitations were known in the art at the time of the effective filing date of the invention, as taught by Zhang et al.
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Regarding claims 7 and 11-13, Zhang et al. teaches a method of estimating fragment position in an alignment using the binding position of either a Watson strand tag or a Crick strand tag (forward or reverse primers) in MACS software for analyzing ChIP-Seq data. For high-quality peaks (fragment clusters), MACS separates their Watson and Crick tags, and aligns them by the midpoint between their Watson and Crick tag centers (if the Watson tag center is to the left of the Crick tag center). The distance between the modes of the Watson and Crick peaks in the alignment is defined as 'd', and MACS shifts all the tags by d/2 toward the 3' ends to the most likely protein-DNA interaction sites. In this example, the value added or subtracted is 63 bp, which is 31.5% of the mean fragment length of 200 bp (R137.2, para. 4-5, Fig. 1a, Fig. 1 of this office action; claim 7: wherein the Representative Position of the nucleic acid fragment is obtained by adding an arbitrary value to a median of the nucleic acid fragment or subtracting the arbitrary value therefrom; claim 11: wherein an arbitrary value is added when a position value is derived based on sequence information aligned in the forward direction and the arbitrary value is subtracted when a position value is derived based on sequence information aligned in the reverse direction; claim 12: wherein the arbitrary value is 30 to 70% of a mean length of the nucleic acid to be analyzed; claim 13: wherein the arbitrary value is 0 to 5 kbp or 0 to 300% of a length of the nucleic acid fragment).
An invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Zhang et al. taught that empirically modeling the distance d and shifting tags by d/2, improved the spatial resolution of the predicted sites over previous algorithms (p. R137.8, para. 1). Therefore, one of ordinary skill in the art would have been motivated to utilize the method of Zhang et al. to the method of detecting chromosomal abnormalities taught by Talkowski et al. in order to improve spatial resolution of the predicted positions of the fragments in the alignment and thus improve mapping of structural variants. Furthermore, one of ordinary skill in the art would predict that the alignment method taught by Zhang et al. could be readily added to the system of Talkowski et al. with a reasonable expectation of success because they both pertain to mapping position of fragments to a reference genome. The invention is therefore prima facie obvious.
Pertaining to claim 8,Talkowski et al. discloses that read-pairs of the sequence data are mapped against a reference genome and categorizing as anomalous, those read pairs that align to genomic sequences separated by significantly greater than or less than the size of the DNA fragments selected for library creation. This method requires calculating the positions of both forward and reverse reads for the sequenced fragment (para. 0010; wherein, in paired-end sequencing, the Representative Position of the nucleic acid fragment is derived based on position values of forward and reverse reads).
Regarding claim 9, Talkowski et al. discloses an example analysis pipeline of cluster identification and filtering wherein reads were filtered to remove those with mapping quality lower than a minimum of Q20 (para. 0015 and 0205; comprising excluding nucleic acid fragments having a mapping quality score of reads below a cutoff value from calculation).
Regarding claim 10, Talkowski et al. teaches that their method of variant detection is compatible with SE sequencing platforms including massively parallel signature sequencing (MPSS), pyrosequencing and microfluidic Sanger sequencing, and thus in these cases, position would be based on one type of position value (forward or reverse). Talkowski et al. also discloses calculating mean and median insert sizes and that in calculating the distance between aligned read pairs, the distance can be determined based on the median and variance of the original size selected fragments (para. 0060, 0066 and 0300; claim 10: wherein in single-end sequencing, the Representative Position of the nucleic acid fragment is derived based on one type of position value of forward or reverse read).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
14. Claims 1 and 3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 8 of copending Application No. 17/780,813. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim 1 of the instant application and claims 4 and 8 of the copending application are directed to measuring the distance between nucleic acid fragments and using the distance to determine if a chromosome abnormality is present and the instant application is generic to the referenced claims. Therefore, claim 1 in the instant application is anticipated by the reference claims (see MPEP 804 (II)(B)(2).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
15. In conclusion, none of the claims are allowable.
E-mail Communications Authorization
16. Per updated USPTO Internet usage policies, Applicant and/or applicant's representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300): "Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file."
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273- 8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
Inquiries
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER J SMITH whose telephone number is (571)272-7801. The examiner can normally be reached Monday-Friday 7:00 AM - 3:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached at (571) 272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.J.S./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
Prosecution Insights